Prediction of pKa values for aliphatic carboxylic acids and alcohols with empirical atomic charge descriptors.

Two quantitative pKa prediction models for aliphatic carboxylic acids and for alcohols were developed by multiple linear-regression (MLR) analysis with empirical atomic descriptors. The acid and alcohol molecules were described by a set of five and four atomic descriptors, respectively. For the pKa model of 1122 aliphatic carboxylic acids, the squared correlation coefficient is 0.813 with a standard error of prediction of 0.423; for the pKa model of 288 alcohols, the squared correlation coefficient is 0.817 with a standard error of prediction of 0.755, respectively. The good predictive abilities of the models obtained were indicated by both cross-validation and by external validation. An atomic descriptor was developed to model the inductive effect of the neighboring atoms for a central atom in a molecule. The ability of the descriptor to measure the inductive effect of substituent groups was demonstrated by a good correlation of this descriptor with Taft sigma* constants in aliphatic carboxylic acids. It provides a new approach to estimate Taft sigma* constants directly from molecular structures. An algorithm using Kohonen neural networks for splitting a data set into a training set and a test set is also presented.